Invertebrate acetylcholinesterase inhibitors
OwnerYuan-Ping Panginventor
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Abstract
Methods for determining invertebrate- and insect-specific, such as mosquito-specific, residues of acetylcholinesterases are provided herein. The methods can be used to design pesticides and insecticides that are specific for the invertebrate or insect (e.g., mosquito) enzymes, resulting in reduced toxicity concerns for mammals. Compositions for inhibiting invertebrate and insect (e.g., mosquito) acetylcholinesterases and methods for preparing the same are also provided.
Claims41
A composition of matter comprising a compound according to Formula I or an acceptable salt or derivative thereof:
- wherein n=0 to 3;
- wherein R1 is selected from:
- a) —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- and
- b) H and one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5;
- wherein R2 is selected from:
- —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5 and H, where n=1 to 10, X4 is as above, and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- wherein R3 is selected from H, CH3, and
- a) —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, where n=1 to 10, X4 is as above, and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- and
- b) one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5;
- wherein R4 is selected from:
- H and one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5;
- and
- wherein X═O or NR5, wherein R5 is selected from H or C1-C5 alkyl.
A composition of matter comprising a compound according to Formula II or an acceptable salt or derivative thereof:
- wherein R1 is H, OMe, OEt, NH2, alkyl(C1-C5), or is selected from:
- A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5;
- wherein R2 and R3 are independently selected from:
- —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CHASH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- wherein R4 is selected from:
- H and one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5.
A composition of matter comprising a compound according to Formula IIIA or Formula IIIB or an acceptable salt or derivative thereof:
- wherein R1 is selected from:
- —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- and
- wherein R2 is selected from:
- H and one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5;
- or
- wherein R1 is selected from:
- —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CHASH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- and
- R2 is selected from H and alkyl(C1-C5);
- and
- R3 is selected from:
- H and one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5.
A composition of matter comprising a compound according to Formula IV or an acceptable salt or derivative thereof:
- wherein R1 is selected from:
- —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- and
- R2 is selected from H and alkyl(C1-C5);
- and
- R3 is selected from:
- H and one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5.
A composition of matter comprising a compound according to Formula V or an acceptable salt or derivative thereof:
- wherein X is O or NH;
- wherein R1 and R2 are independently selected from H and substituted or unsubstituted, saturated or unsaturated, cyclic or linear alkyl or heteroalkyl moieties and substituted or unsubstituted aryl or heteroaryl moieties, or together R1 and R2 form a saturated or unsaturated cyclic alkyl or heteroalkyl moiety, or an aryl or heteroaryl moiety, any of which may be substituted or unsubstituted (e.g., with a fused aryl ring (which may be substituted with R4 and/or R5 moieties), or with alkyl moieties (which may be substituted with R4 and R5 moieties));
- wherein R3 is selected from H, a substituted or unsubstituted alkyl, aryl, or amine moiety (e.g., substituted with R6 and/or R7 or is R8) or is selected from one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5;
- wherein R4 is selected from H and one of the moieties A, B, C, D, and E set forth above for R3;
- wherein R5 is selected from:
- —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- wherein R6 and R7 are independently selected from H or alkyl(C1-C5);
- and
- wherein R8 is selected from CH3 and CH2CH3.
A composition of matter comprising a compound according to Formula VI or an acceptable salt or derivative thereof:
- wherein R2 is selected from:
- wherein R1 is selected from —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2O, —(CH2)nX4, —(CHASH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- and
- wherein R3 is selected from H and is selected from one of the moieties A, B, C, D, and E.
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5.
A composition of matter comprising a compound according to Formula VII or an acceptable salt or derivative thereof:
- wherein R1 and R3 are independently selected from H or alkyl(C1-C5);
- wherein R2 is selected from:
- —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- and
- wherein R4 is selected from H and from one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5.
A composition of matter comprising a compound according to Formula VIII or an acceptable salt or derivative thereof:
- wherein R1 is selected from H, halogen, and one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5;
- R2 is selected from —(CH2)nI, —(CH2)nBr, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5, (CH2)nCOCH2I, —(CH2)nCOCH2Br, —(CH2)nCOCH2Cl, —(CH2)nNHCOCH2I, —(CH2)nNHCOCH2Br, —(CH2)nNHCOCH2Cl, —(CH2)nCH═CHCH2I, —(CH2)nCH═CHCH2Br, —(CH2)nCH═CHCH2Cl, —(CH2)nPhCH2I, —(CH2)nPhCH2Br, —(CH2)nPhCH2Cl, —(CH2)nX4, —(CH2)nSH, —(CH2)nS—SX5 and H, where n=1 to 10;
- X4 is selected from:
- and X5=alkyl(C1-C5) or —(O)2alkyl(C1-C5);
- wherein R3, R4 together form a saturated or unsaturated cyclic alkyl or cyclic heteroalkyl moiety, which may be substituted (e.g., with one or more R2, R5, or R6 groups), or together form an aryl or heteroaryl moiety which may be substituted (e.g., with one or more R2, R5, or R6 groups)
- wherein R5 is selected from H or alkyl(C1-C5);
- wherein R6 is selected from H and one of the moieties A, B, C, D, and E:
- wherein E's R1═H or Me;
- and n for A-E ranges from 0 to 5;
- and
- wherein X is selected from O, S, and NH.
A computer-assisted method of generating a test inhibitor of the acetylcholinesterase site activity of an invertebrate acetylcholinesterase (AChE) polypeptide, the method using a programmed computer comprising a processor and an input device, the method comprising:
- (a) inputting on the input device data comprising a structure of an acetylcholinesterase active site of an invertebrate AChE polypeptide;
- (b) docking into the active site a test inhibitor molecule using the processor;
- and
- (c) determining, based on the docking, whether the test inhibitor molecule would be capable of interacting with a residue of the invertebrate AChE polypeptide corresponding to Arg339 of AgAChE.
A method of generating a compound that inhibits the acetylcholinesterase site activity of the Anopheles gambiae AChE polypeptide, the method comprising:
- (a) providing a three-dimensional structure of the Anopheles gambiae AChE polypeptide acetylcholinesterase active site;
- and
- (b) designing, based on the three-dimensional structure, a test compound capable of interacting with Arg339.
An insecticidal composition comprising a compound, or salt or derivative thereof, according to any one of claims 1-8, 29 or 30 and a carrier.
A pesticidal composition comprising a compound, or salt or derivative thereof, according to any one of claims 1-8, 29 or 30 and a carrier.
A composition of matter comprising a compound according to Formula IX or an acceptable salt or derivative thereof:
- wherein R1, R2, R3 and R4 are independently selected from is selected from H or alkyl(C1-C5);
- X is selected from halo and pseudohalo;
- and
- n is an integer from 5 to 25.
A composition of matter comprising a compound according to Formula X or an acceptable salt or derivative thereof:
- wherein X is selected from halo and pseudohalo;
- Y is an salt;
- and
- n is an integer from 5 to 15.
A computer-assisted method of generating a test inhibitor of the acethylcholinesterase site activity of an invertebrate acetylcholinesterase (AChE) polypeptide, the method comprising:
- (a) receiving on a computing device data comprising a structure of an acetylcholinesterase active site of an invertebrate AChE polypeptide;
- (b) docking into the docking box a test inhibitor molecule using the computing device;
- and
- (c) determining, using the computing device, based on the docking, whether the test inhibitor molecule would be capable of interacting with a residue of the invertebrate AChE polypeptide corresponding to Arg339 of AgAChE.
A computer-assisted method of generating a test inhibitor of the acethylcholinesterase site activity of an invertebrate acetylcholinesterase (AChE) polypeptide, the method comprising:
- (a) receiving on a computing device data comprising a structure of an acetylcholinesterase active site of an invertebrate AChE polypeptide;
- (b) docking into the docking box a test inhibitor molecule using the computing device;
- and
- (c) determining, using the computing device, based on the docking, whether the test inhibitor molecule would be capable of interacting with a residue of the invertebrate AChE polypeptide corresponding to Cys289 of greenbug AChE.
A computer-assisted method of generating a test inhibitor of the acetylcholinesterase site activity of an invertebrate acetylcholinesterase (AChE) polypeptide, the method using a programmed computer comprising a processor and an input device, the method comprising:
- (a) inputting on the input device data comprising a structure of an acetylcholinesterase active site of an invertebrate AChE polypeptide;
- (b) docking into the active site a test inhibitor molecule using the processor;
- and
- (c) determining, based on the docking, whether the test inhibitor molecule would be capable of interacting with a residue of the invertebrate AChE polypeptide corresponding to Cys289 of greenbug AChE.
A method of generating a compound that inhibits the acetylcholinesterase site activity of the greenbug AChE polypeptide, the method comprising:
- (a) providing a three-dimensional structure of the greenbug AChE polypeptide acetylcholinesterase active site;
- and
- (b) designing, based on the three-dimensional structure, a test compound capable of interacting with Cys289.
Dependencies are inferred from the claim text.